Lymphatic Function and Immune Regulation in Health and Disease

Abstract

Get full access to this article

View all access options for this article.

References

Drayton

et al. Lymphoid organ development: From ontogeny to neogenesis. Nat Immunol, 2006; 7:344–353.

Baluk

et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med, 2007; 204:2349–2362.

Oliver

, Alitalo

. The lymphatic vasculature: Recent progress and paradigms. Annu Rev Cell Dev Biol, 2005; 21:457–483.

Witte

et al. Lymphangiogenesis and lymphangiodysplasia: From molecular to clinical lymphology. Microsc Res Tech, 2001; 55:122–145.

Pflicke

, Sixt

. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med, 2009; 206:2925–2935.

Randolph GJ

Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol, 2005; 5:617–628.

Schumann

et al. Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity, 2010; 32:703–713.

Miteva

et al. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ Res, 2010; 106:920–931.

Weber

et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science, 2013; 339:328–332.

10.

Nitschke

et al. Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation. Blood, 2012; 120:2249–2258.

11.

Skalak

, Schmid-Schonbein

, Zweifach

. New morphological evidence for a mechanism of lymph formation in skeletal muscle. Microvasc Res, 1984; 28:95–112.

12.

Schmid-Schonbein

. Microlymphatics, lymph flow. Physiol Rev, 1990; 70:987–1028.

13.

Breslin

et al. Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism. Am J Physiol Heart Circ Physiol, 2007; 293:H709–718.

14.

Eisenhoffer

, Yuan

, Johnston

. Evidence that the L-arginine pathway plays a role in the regulation of pumping activity in bovine mesenteric lymphatic vessels. Microvasc Res, 1995; 50:249–259.

15.

Gasheva

, Zawieja

, Gashev

. Contraction-initiated NO-dependent lymphatic relaxation: A self-regulatory mechanism in rat thoracic duct. J Physiol, 2006; 575:821–832.

16.

Hagendoorn

et al. Endothelial nitric oxide synthase regulates microlymphatic flow via collecting lymphatics. Circ Res, 2004; 95:204–209.

17.

Lahdenranta

et al. Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res, 2009; 69:2801–2808.

18.

Bohlen

et al. Phasic contractions of rat mesenteric lymphatics increase basal and phasic nitric oxide generation in vivo. Am J Physiol Heart Circ Physiol, 2009; 297:H1319–1328.

19.

Bohlen

, Gasheva

, Zawieja

. Nitric oxide formation by lymphatic bulb and valves is a major regulatory component of lymphatic pumping. Am J Physiol Heart Circ Physiol, 2011; 301:H1897–1906.

20.

Fukumura

, Kashiwagi

, Jain

. The role of nitric oxide in tumour progression. Nat Rev Cancer, 2006; 6:521–534.

21.

Kashiwagi

et al. Perivascular nitric oxide gradients normalize tumor vasculature. Nat Med, 2008; 14:255–257.

22.

Shirasawa

, Ikomi

, Ohhashi

. Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat mesentery in vivo. Am J Physiol Gastrointest Liver Physiol, 2000; 278:G551–556.

23.

Liao

et al. Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci USA, 2011; 108:18784–18789.

24.

et al. Glucose and glucose transporters regulate lymphatic pump activity through activation of the mitochondrial ATP-sensitive K+ channel. J Physiol Sci, 2008; 58:249–261.

25.

Johnston

, Feuer

. Suppression of lymphatic vessel contractility with inhibitors of arachidonic acid metabolism. J Pharmacol Exp Ther, 1983; 226:603–607.

26.

Tal

et al. DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J Exp Med, 2011; 208:2141–2153.

27.

von Andrian

, M'Rini

. In situ analysis of lymphocyte migration to lymph nodes. Cell Adhes Commun, 1998; 6:85–96.

28.

Anderson

, Anderson

. Studies on the structure and permeability of the microvasculature in normal rat lymph nodes. Am J Pathol, 1975; 80:387–418.

29.

Hemmerich

, Butcher

, Rosen

. Sulfation-dependent recognition of HEV-ligands by L-selectin and MECA-79, an adhesion-blocking mAb. J Exp Med, 1994; 180:2219–2226.

30.

Hemmerich

et al. Sulfation of L-selectin ligands by an HEV-restricted sulfotransferase regulates lymphocyte homing to lymph nodes. Immunity, 2001; 15:237–247.

31.

Homeister

et al. The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing. Immunity, 2001; 15:115–126.

32.

Hiraoka

et al. Core 2 branching beta1,6-N-acetylglucosaminyltransferase and high endothelial venule-restricted sulfotransferase collaboratively control lymphocyte homing. J Biol Chem, 2004; 279:3058–3067.

33.

Hiraoka

et al. A novel, high endothelial venule-specific sulfotransferase expresses 6-sulfo sialyl Lewis(x), an L-selectin ligand displayed by CD34. Immunity, 1999; 11:79–89.

34.

Bajenoff

, Granjeaud

, Guerder

. The strategy of T cell antigen-presenting cell encounter in antigen-draining lymph nodes revealed by imaging of initial T cell activation. J Exp Med, 2003; 198:715–724.

35.

Mempel

, Henrickson

, Von Andrian

. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature, 2004; 427:154–159.

36.

Cyster

. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol, 2005; 23:127–159.

37.

et al. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med, 2005; 201:291–301.

38.

Liao

, Ruddle

. Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol, 2006; 177:3369–3379.

39.

Mebius

et al. Expression of GlyCAM-1, an endothelial ligand for L-selectin, is affected by afferent lymphatic flow. J Immunol, 1993; 151:6769–6776.

40.

Mebius

et al. The influence of afferent lymphatic vessel interruption on vascular addressin expression. J Cell Biol, 1991; 115:85–95.

41.

Hendriks

, Duijvestijn

, Kraal

. Rapid decrease in lymphocyte adherence to high endothelial venules in lymph nodes deprived of afferent lymphatic vessels. Eur J Immunol, 1987; 17:1691–1695.

42.

Swarte

et al. Regulation of fucosyltransferase-VII expression in peripheral lymph node high endothelial venules. Eur J Immunol, 1998; 28:3040–3047.

43.

Drayson

, Ford

. Afferent lymph and lymph borne cells: Their influence on lymph node function. Immunobiology, 1984; 168:362–379.

44.

Hendriks

, Eestermans

. Disappearance and reappearance of high endothelial venules and immigrating lymphocytes in lymph nodes deprived of afferent lymphatic vessels: A possible regulatory role of macrophages in lymphocyte migration. Eur J Immunol, 1983; 13:663–669.

45.

Gretz

et al. Sophisticated strategies for information encounter in the lymph node: The reticular network as a conduit of soluble information and a highway for cell traffic. J Immunol, 1996; 157:495–499.

46.

Gretz

, Anderson

, Shaw

. Cords, channels, corridors, conduits: Critical architectural elements facilitating cell interactions in the lymph node cortex. Immunol Rev, 1997; 156:11–24.

47.

Gretz

et al. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J Exp Med, 2000; 192:1425–1440.

48.

Larsen

et al. The neutrophil-activating protein (NAP-1) is also chemotactic for T lymphocytes. Science, 1989; 243:1464–1466.

49.

Anderson

, Anderson

. Lymphocyte emigration from high endothelial venules in rat lymph nodes. Immunology, 1976; 31:731–748.

50.

Mebius

et al. The functional activity of high endothelial venules: A role for the subcapsular sinus macrophages in the lymph node. Immunobiology, 1991; 182:277–291.

51.

Moussion

, Girard

. Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature, 2011; 479:542–546.

52.

Iannacone

et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature, 2010; 465:1079–1083.

53.

Roozendaal

et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity, 2009; 30:264–276.

54.

Phan

et al. Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation. Nat Immunol, 2009; 10:786–793.

55.

Mandl

et al. Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naive CD4+ and CD8+ T cells. Proc Natl Acad Sci USA, 2012; 109:18036–18041.

56.

Braun

et al. Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. Nat Immunol, 2011; 12:879–887.

57.

Allenspach

et al. Migratory and lymphoid-resident dendritic cells cooperate to efficiently prime naive CD4 T cells. Immunity, 2008; 29:795–806.

58.

Bouneaud

, Kourilsky

, Bousso

. Impact of negative selection on the T cell repertoire reactive to a self-peptide: A large fraction of T cell clones escapes clonal deletion. Immunity, 2000; 13:829–840.

59.

Wilson

et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood, 2003; 102:2187–2194.

60.

Steinman

et al. Dendritic cell function in vivo during the steady state: A role in peripheral tolerance. Ann NY Acad Sci, 2003; 987:15–25.

61.

von Andrian

, Mempel

. Homing and cellular traffic in lymph nodes. Nat Rev Immunol, 2003; 3:867–878.

62.

Hemmi

et al. Skin antigens in the steady state are trafficked to regional lymph nodes by transforming growth factor-beta1-dependent cells. Int Immunol, 2001; 13:695–704.

63.

Scheinecker

et al. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med, 2002; 196:1079–1090.

64.

Huang

et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J Exp Med, 2000; 191:435–444.

65.

Wilson

, Villadangos

. Lymphoid organ dendritic cells: Beyond the Langerhans cells paradigm. Immunol Cell Biol, 2004; 82:91–98.

66.

Wilson

, El-Sukkari

, Villadangos

. Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Blood, 2004; 103:2187–2195.

67.

Cavanagh

, Von Andrian

. Travellers in many guises: The origins and destinations of dendritic cells. Immunol Cell Biol, 2002; 80:448–462.

68.

Stoitzner

et al. Migratory Langerhans cells in mouse lymph nodes in steady state and inflammation. J Invest Dermatol, 2005; 125:116–125.

69.

Lee

et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol, 2007; 8:181–190.

70.

Nichols

et al. Deletional self-tolerance to a melanocyte/melanoma antigen derived from tyrosinase is mediated by a radio-resistant cell in peripheral and mesenteric lymph nodes. J Immunol, 2007; 179:993–1003.

71.

Cohen

et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med, 2010; 207:681–688.

72.

Angeli

et al. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity, 2006; 24:203–215.

73.

Kim

et al. Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol, 2009; 175:1733–1745.

74.

Jeon

et al. Profound but dysfunctional lymphangiogenesis via vascular endothelial growth factor ligands from CD11b+ macrophages in advanced ovarian cancer. Cancer Res, 2008; 68:1100–1109.

75.

Kataru

et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood, 2009; 113:5650–5659.

76.

Maruyama

et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest, 2005; 115:2363–2372.

77.

Halin

et al. VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood, 2007; 110:3158–3167.

78.

Kataru

et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity, 2011; 34:96–107.

79.

Wang

. Activated macrophage-mediated endogenous prostaglandin and nitric oxide-dependent relaxation of lymphatic smooth muscles. Jpn J Physiol, 1997; 47:93–100.

80.

Hoke

et al. Selective modulation of the expression of L-selectin ligands by an immune response. Curr Biol, 1995; 5:670–678.

81.

Mebius

et al. The function of high endothelial venules in mouse lymph nodes stimulated by oxazolone. Immunology, 1990; 71:423–427.

82.

Mueller

et al. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science, 2007; 317:670–674.

83.

Mallon

, Ryan

. Lymphedema and wound healing. Clin Dermatol, 1994; 12:89–93.

84.

Witte

, Witte

. Disorders of lymph flow. Acad Radiol, 1995; 2:324–334.

85.

Golshan

, Smith

. Prevention and management of arm lymphedema in the patient with breast cancer. J Support Oncol, 2006; 4:381–386.

86.

Morrell

et al. Breast cancer-related lymphedema. Mayo Clin Proc, 2005; 80:1480–1484.

87.

Szuba

, Rockson

. Lymphedema: Anatomy, physiology and pathogenesis. Vasc Med, 1997; 2:321–326.

88.

Alitalo

, Tammela

, Petrova

. Lymphangiogenesis in development and human disease. Nature, 2005; 438:946–953.

89.

Kerjaschki

et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med, 2006; 12:230–234.

90.

Dietrich

et al. Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol, 2010; 184:535–539.

91.

Paavonen

et al. Vascular endothelial growth factors C and D and their VEGFR-2 and 3 receptors in blood and lymphatic vessels in healthy and arthritic synovium. J Rheumatol, 2002; 29:39–45.

92.

von der Weid

, Rainey

. Review article: Lymphatic system and associated adipose tissue in the development of inflammatory bowel disease. Aliment Pharmacol Ther, 2010; 32:697–711.

93.

Mumprecht

et al. In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography. Cancer Res, 2010; 70:8842–8851.

94.

Qian

et al. Preparing the "soil": The primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res, 2006; 66:10365–10376.

95.

Gabrilovich

, Nagaraj

. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol, 2009; 9:162–174.

96.

Murdoch

et al. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer, 2008; 8:618–631.

97.

Padera

et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science, 2002; 296:1883–1886.

98.

Mumprecht

, Detmar

. Lymphangiogenesis and cancer metastasis. J Cell Mol Med, 2009; 13:1405–1416.

99.

Jain

. Molecular regulation of vessel maturation. Nat Med, 2003; 9:685–693.

100.

Kesler

et al. Lymphatic vessels in health and disease. Wiley Interdiscip Rev Syst Biol Med, 2013; 5:111–124.

101.

Tammela

, Alitalo

. Lymphangiogenesis: Molecular mechanisms and future promise. Cell, 2010; 140:460–476.

102.

Sauter

et al. Consequences of cell death: Exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med, 2000; 191:423–434.

103.

Albert

et al. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med, 1998; 188:1359–1368.

104.

Asano

et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity, 2011; 34:85–95.

105.

Veronesi

et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med, 2003; 349:546–553.

106.

Morton

et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med, 2006; 355:1307–1317.

107.

Swartz

, Lund

. Lymphatic and interstitial flow in the tumour microenvironment: Linking mechanobiology with immunity. Nat Rev Cancer, 2012; 12:210–219.

108.

Padera

et al. Pathology: Cancer cells compress intratumour vessels. Nature, 2004; 427:695.

109.

Jain

, Tong

, Munn

. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: Insights from a mathematical model. Cancer Res, 2007; 67:2729–2735.

110.

Hoshida

et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: Therapeutic implications. Cancer Res, 2006; 66:8065–8075.

111.

Lee

et al. Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection. J Exp Med, 2009; 206:359–370.

112.

Babu

, Nutman

. Immunopathogenesis of lymphatic filarial disease. Semin Immunopathol, 2012; 34:847–861.

113.

Stuht

et al. Lymphatic neoangiogenesis in human renal allografts: Results from sequential protocol biopsies. Am J Transplant, 2007; 7:377–384.

114.

Yin

et al. Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation, 2011; 92:25–30.

115.

Ling

et al. Crucial role of corneal lymphangiogenesis for allograft rejection in alkali-burned cornea bed. Clin Experiment Ophthalmol, 2009; 37:874–883.

116.

Fletcher

et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med, 2010; 207:689–697.